title: Estrogen receptor α or β loss in the colon of Min/+ mice promotes crypt expansion and impairs TGFβ and HNF3β signaling.
abstract: Adenomatous polyposis coli (APC)-regulated Wnt and transforming growth factor-β (TGFβ) signaling cooperate in the intestine to maintain normal enterocyte functions. Human clinical trials showed that estrogen [17β-estradiol (E2)], the ligand of nuclear receptors estrogen receptor α (ERα) and ERβ, inhibited colorectal cancer (CRC) in women. Consistent with this finding, we reported that E2, ERα and ERβ suppressed intestinal tumorigenesis in the C57BL/6J-Min/+ (Min/+) mouse, a CRC model. Here, we extended our results with further comparisons of colon and small intestine from intact female Apc (+/+) (WT), Min/+ and ER-deficient Min/+ mice. In the colon of ER-deficient Min/+ mice, ER loss reduced TGFβ signaling in crypt base cells as evidenced by minimal expression of the effectors Smad 2, 3 and 4 in these strains. We also found reduced expression of Indian hedgehog (Ihh), bone morphogenetic protein 4 and hepatocyte nuclear factor 3β or FoxA2, factors needed for paracrine signaling between enterocytes and mesenchyme. In proximal colon, ER loss produced a >10-fold increased incidence of crypt fission, a marker for wound healing and tumor promotion. These data, combined with our previous work detailing the specific roles of E2, ERα and ERβ in the colon, suggest that ER activity helps to maintain the intestinal stem cell (ISC) microenvironment by modulating epithelial-stromal crosstalk in ways that regulate cytokine, Wnt and Ihh availability in the extracellular matrix (ECM).
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Rian M
authors.initials: RM
authors.lastname: Hasson
authors.forename: Alexandra
authors.initials: A
authors.lastname: Briggs
authors.forename: Adelaide M
authors.initials: AM
authors.lastname: Carothers
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Davids
authors.forename: Jiping
authors.initials: J
authors.lastname: Wang
authors.forename: Sara H
authors.initials: SH
authors.lastname: Javid
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Cho
authors.forename: Monica M
authors.initials: MM
authors.lastname: Bertagnolli
mesh_terms: D058739:Aberrant Crypt Foci / Q000378:metabolism / Q000473:pathology; D000818:Animals; D060833:Cellular Microenvironment; D003106:Colon / Q000378:metabolism* / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019879:Paneth Cells / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D051901:Smad4 Protein / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C496503:Foxa2 protein, mouse; D053823:Hedgehog Proteins; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D016212:Transforming Growth Factor beta; C514061:ihh protein, mouse; D051542:Hepatocyte Nuclear Factor 3-beta